The present invention relates generally to the field of use of alkyl, alkoxyl, halogenyl, or hydroxyl substituted dicinnamoylquinides. Specifically, the present invention relates to the use of the above-mentioned compounds to treat diseases or conditions that improve from either an acute or chronic increase in adenosine levels.
Adenosine is a neuromodulator known to produce profound effects on blood flow, neurotransmission, cellular functions, and metabolism. Intracellular levels of adenosine are disclosed to be maintained by an active transport of adenosine across the cell membrane by means of a carrier-mediated, saturable nucleoside transporter, consisting of a 50 kDa protein in the form of a dimer (Thorn and Jarvis, Gen Pharmacol 27, 613-620 (1996)). This transporter protein is widely distributed in thalamic, cortical, and particularly in striatal neurons in the human brain (Glass et al, Brain Res 710, 79-91 (1996), Jennings et al, Neuropharmacol 40, 722-731 (2001)), where it regulates adenosine-dopamine interactions (Dunwiddie and Masino, Ann Rev Neurosci 24, 31-55 (2001)). Of all mammals studied, the human transporter is disclosed to be one of the most sensitive to adenosine (Hammond, N-S Arch Pharmacol 361, 373-382 (2000)), resulting in an extremely short half-life of adenosine in blood. Inhibition of the adenosine transporter is disclosed to prevent the intracellular metabolism of adenosine and prolongs the presence of high levels of adenosine (Thorn and Jarvis, Gen Pharmacol 27, 613-620 (1996). This increased level of adenosine in brain causes stimulation of adenosine receptor subtypes, similar to the effects seen from unselective adenosine receptor agonizes. Activation of the adenosine A2B receptor was found to increase vascular endothelial growth factor production, resulting in angiogenic neovascularization (Grant et al, Circ Res 85, 699-706 (1999). Recent studies have demonstrated that agonists for the adenosine A3 receptor have antiinflammatory properties (Fishman et al, J. Cell Physiol 183, 393-398 (2000)). Both agonists at the adenosine A1 and A3 receptors have shown cardioprotective activity in man (Baraldi et al, Ed Res Rev 20, 103-128 (2000)), and conjugate compounds of potent adenosine A1 and A3 receptor agonists have shown full cardioprotection in a myocyte model of ischemia (Jacobson et al, J. Biol Chem 275, 30272-30279 (2000)).
Based on the discovery that certain naturally occurring 4-hydroxycinnamoyl di-esters of quinic acid gamma-lactone in roasted coffee (Hucke et al, Z. Lebensm Unters Forsch 180, 479-484 (1985)), but not in tea or any other caffeine containing beverages, inhibits the human adenosine transporter (de Pails et al, Eur J Pharmacol 442, 213-221 (2002)), the present invention provides, in part, methods of using 3,4-disubstituted cinnamoyl esters of quinic acid 1,5-lactone, exemplified by Formula 1, having no substituent, or a halogen atom or a hydroxyl, alkyl or alkoxyl group in either of the aromatic 3-, 4- and 5-positions to inhibit the human adenosine transporter. By inhibiting the adenosine transporter, the metabolism of intracellular adenosine is prevented resulting in increased levels of extracellular adenosine.
Methods are provided for using compounds corresponding to Formula 1 (FIG. 1) that block the normal operation of the adenosine transporter, and preferably, result in a higher level of extra-cellular adenosine.
The present invention also provides a method of producing compounds corresponding to Formula 1.
Formula 1 is shown below: 
The present invention also provides a method of delivering the compounds corresponding to Formula 1 in order to maintain a systemic level at effective concentrations.
The present invention provides fortified food products having therapeutically effective amounts of a compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6 are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, or an alkoxyl group. Such fortified food product provides the therapeutic effect of partially or completely inhibiting the adenosine transporter.
No aspect or embodiment of the present invention is bound by theory or mechanism. Various features and advantages of the invention will be apparent from the following detailed description and from the claims.